Immunity
Volume 52, Issue 4, 14 April 2020, Pages 668-682.e7
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Article
The Unfolded Protein Response Mediator PERK Governs Myeloid Cell-Driven Immunosuppression in Tumors through Inhibition of STING Signaling

https://doi.org/10.1016/j.immuni.2020.03.004Get rights and content
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Highlights

  • Tumor-infiltrating MDSCs demonstrate increased activation of PERK signaling

  • PERK ablation in MDSCs elicits anti-tumor T cells and synergizes with immunotherapy

  • Deletion of PERK reprograms tumor MDSC functionality by blunting NRF2 signaling

  • Reduced NRF2 primes STING-to-type I IFN axis in PERK-null MDSCs via cytosolic mtDNA

Summary

The primary mechanisms supporting immunoregulatory polarization of myeloid cells upon infiltration into tumors remain largely unexplored. Elucidation of these signals could enable better strategies to restore protective anti-tumor immunity. Here, we investigated the role of the intrinsic activation of the PKR-like endoplasmic reticulum (ER) kinase (PERK) in the immunoinhibitory actions of tumor-associated myeloid-derived suppressor cells (tumor-MDSCs). PERK signaling increased in tumor-MDSCs, and its deletion transformed MDSCs into myeloid cells that activated CD8+ T cell-mediated immunity against cancer. Tumor-MDSCs lacking PERK exhibited disrupted NRF2-driven antioxidant capacity and impaired mitochondrial respiratory homeostasis. Moreover, reduced NRF2 signaling in PERK-deficient MDSCs elicited cytosolic mitochondrial DNA elevation and, consequently, STING-dependent expression of anti-tumor type I interferon. Reactivation of NRF2 signaling, conditional deletion of STING, or blockade of type I interferon receptor I restored the immunoinhibitory potential of PERK-ablated MDSCs. Our findings demonstrate the pivotal role of PERK in tumor-MDSC functionality and unveil strategies to reprogram immunosuppressive myelopoiesis in tumors to boost cancer immunotherapy.

Keywords

tumor immunity
MDSCs
PERK
unfolded protein responses
NRF2
STING
type I IFN
ER stress

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